This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Type 1 diabetes in humans is a chronic, slowly progressive autoimmune disease for which immunosuppressive treatments are being explored. Stiller and colleagues [1] first showed that Cyclosporine maintained C-peptide at 1 year from diagnosis in new onset patients but nephrotoxicity limited its use. Our choice of Mycophenolate mofetil (MMF) and Daclizumab, anti-IL2 Receptor antibody, for interventions in new onset type 1 diabetes is based on their effectiveness for transplants and autoimmunity. We predict that MMF, alone or in combination with anti-IL2R antibody, will cause activation-induced cell death of self-reactive lymphocytes. If correct, the hypothesis predicts that MMF will halt islet cell destruction in type 1 diabetes. The anti-IL2R antibody is particularly effective in arresting rejection episodes - presumably through starving activated T cells of IL2. Since type 1 diabetic subjects have an increased number of activated T cells, we hypothesize that the anti-IL2 Receptor antibody will target these potentially autoreactive cells while sparing the resting na ve and memory T cells. We predict meaningful preservation of islet function with minimal immune system side effects over the 4-year course of this study. We have powered our study from previous work defining the rate of beta cell loss in the absence of immunosuppression. Our approach is predicated on the view that an immunosuppressive intervention has to reduce the loss of islet cells to < 50% of control over 2 years to have potential usefulness.
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